Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) enzymes convert corticosterone and cortisol to 11-dehydrocorticosterone and cortisone, and are thought to convey extrinsic specificity to the mineralocorticoid receptor by limiting access of the relatively more abundant glucocorticoids to it. Two different 11 beta-hydroxysteroid dehydrogenases (11 beta-HSD) have been described and cloned. The liver-type, NADP(+)-dependent 11 beta-HSD-1, has an affinity in the micromolar range and bidirectional activity. The NAD(+)-dependent 11 beta-HSD-2 has a higher affinity, in the nanomolar range, and exhibits only oxidase activity. 11 beta-HSD-2, because of its affinity and co-localization with the mineralocorticoid receptor, is likely to serve as the "gatekeeper" for the mineralocorticoid receptor in the kidney. Although the rat kidney expresses both isoforms, only the high-affinity, NAD(+)-dependent 11 beta-HSD-2 has been reported in the sheep kidney. We found both 11 beta-HSD NAD(+)- and NADP(+)-dependent activities in sheep kidney to be present. The NAD(+)-dependent activity exhibited a Km similar to that reported in the literature, 3.85 +/- 1.28 nM for corticosterone and 21.3 +/- 5.8 for cortisol, was distributed in approximately equal amounts between microsomes and nuclei, and was unidirectional, converting corticosterone to 11-dehydrocorticosterone. The enzyme exhibited prominent substrate inhibition. The NADP(+)-dependent activity had a Km for corticosterone of 4 +/- 1.3 nM for a Km for cortisol of 35.2 +/- 2 nM, 100-fold lower than that described for the 11 beta-HSD-1 in the liver of sheep and other species, and was more prevalent in the microsomes than the nuclei. This enzyme was not inhibited by its substrate. The NAD(+)-dependent activity was approximately 3-10 times greater than the NADP(+)-dependent activity when incubated with 5 nM corticosterone substrate, but had similar activity when incubated with 100 nM substrate concentrations. CHOP cells (a modified Chinese hamster ovary cell line) transiently transfected with the sheep 11 beta-HSD-2 plasmid exhibited a marked preference for NAD+ as co-factor. Oxidation of corticosterone by transfected cells in the presence of NADP+ was present, but minimal; NADP+ did not support the metabolism of cortisol, the primary glucocorticoid of sheep. These data suggest the existence of another NADP(+)-dependent enzyme, 11 beta-HSD-3, which, because of its high affinity and unidirectional oxidase activity, may play a physiological role in the modulation of glucocorticoid binding to both the mineralocorticoid and glucocorticoid receptors.
Steroids 1997 May
PMID:The sheep kidney contains a novel unidirectional, high affinity NADP(+)-dependent 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD-3). 917 32

These studies investigated whether treatment with carbenoxolone (CBX), an inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), resulted in an enhanced mineralocorticoid response to endogenous or infused cortisol. In conscious sodium replete sheep with a parotid fistula, infusion of CBX (40 mg/h for 10 days) did not increase mean arterial pressure, or change sodium and potassium status or plasma renin concentration, but significantly increased the half-life of 1,2[3H] cortisol from 18.6 +/- 4.0 to 38.8 +/- 3.9 min (p < 0.05) and reduced the blood clearance rate of cortisol (BCR) from 31 +/- 3 to 15 +/- 4 L/h (p < 0.01). The reduction in cortisol BCR was associated with reduction in cortisol secretion rate from 433 +/- 116 to 181 +/- 79 nmol/h (p < 0.01). Cortisol (8 mg/h) for 5 days increased mean arterial pressure (from 83 +/- 2 to 101 +/- 5 mmHg, p < 0.001) and caused natriuresis, hypokalaemia and hyperglycaemia. These responses were unaltered when cortisol was infused from the fifth to the tenth day of CBX infusion. These findings suggest that in sheep, carbenoxolone is either a less potent inhibitor of 11 beta-HSD2 than in other species or 11 beta-HSD2 may not be the only mechanism, which determines the specificity of the MR.
Steroids 1998 Feb
PMID:Carbenoxolone does not cause a syndrome of mineralocorticoid excess in sheep. 951 20

The presence of an 11 beta-hydroxyl group is essential for the anti-inflammatory and immunosuppressive effects of glucocorticoids. Interconversion of the 11 beta-hydroxyl into the corresponding 11 beta-keto group and vice versa by 11 beta-hydroxysteroid-dehydrogenase (11 beta-HSD) may thus play a pivotal role in the efficacy of these steroids. Therefore, we have compared the metabolism of the endogenous glucocorticoid cortisol (F) with that of synthetic 9 alpha-fluorinated steroids by 11 beta-HSDs in humans in vivo and in vitro. Whereas 30% of the free steroids in urine after oral administration of 5 mg of F is F itself and 70% the inactive keto-product cortisone (E), the urinary excretion of an identical dose of oral 9 alpha-fluorocortisol (9 alpha FF) is 90% 9 alpha FF and 10% inactive 9 alpha-fluorocortisone (9 alpha FE). Kidney slices similarly convert F much faster to E than 9 alpha FF to 9 alpha FE; conversely, renal 11 beta-reduction of 9 alpha FE to 9 alpha FF is much more effective than that of E to F. Kinetic analyses in human kidney cortex microsomes prove that the preference of fluorinated steroids for reduction in human kidney slices is catalyzed by 11 beta-HSD type II: the NADH-dependent conversion of 11-dehydro-dexamethasone (DH-D), another fluorinated steroid, to dexamethasone (D) is very effective (high affinity, high Vmax), whereas reduction of E to F is very slow. In human liver microsomes (11 beta-HSD type I), nonfluorinated (E) and fluorinated 11-dehydrosteroids (DH-D) are both reduced to their corresponding active 11-hydroxyderivatives but with a Michaelis-Menten constant about 20-fold higher than for kidney microsomes (11 beta-HSD-II). Our results suggest that the decreased renal 11 beta-oxidation of 9 alpha-fluorinated steroids may offer pharmacokinetic advantages for renal immunosuppression. Furthermore, administration of fluorinated 11-dehydrosteroids is a new and exciting idea in glucocorticoid therapy in that small amounts of oral DH-D may pass the liver largely unmetabolized (11 beta-HSD-I has low affinity for such steroids) and may then be activated to D by high-affinity 11 beta-HSD-II, thus allowing selective immunosuppression in organs expressing 11 beta-HSD-II (kidney and colon).
Steroids
PMID:Metabolism of synthetic corticosteroids by 11 beta-hydroxysteroid-dehydrogenases in man. 961 84

The adrenal gland is involved in the control of urinary sodium excretion mainly via the secretion of the mineralocorticoid aldosterone. Although under certain conditions glucocorticoid seem to be also involved in the regulation of sodium homeostasis, there are contradictory reports on the relationship between cortisol secretion and sodium intake. Given recent findings linking regulation of physiological activity of steroids to the activity of specific enzymatic pathways, we have examined changes in urinary excretion of cortisol and its metabolites in eight healthy volunteers on a low sodium diet. Urinary steroids were measured with specific radioimmunoassays after extraction and chromatography (F and E) or after dilution (THF and THE). Excretion of cortisol (124 +/-41 nmol/day) was significantly lower on Day 2 (86 +/- 27 nmol/day, p < 0.01) and Day 7 (85 +/- 25 nmol/day, p < 0.01) of sodium restriction. On the same samples calculated ratios of THF/F (55 +/- 15; 61 +/- 22; 68 +/- 21) and E/F (2.5 +/- 0.6; 2.8 +/- 1.4; 3.0 +/- 1.3) reflecting the activity of 5 beta-reductase and 11 beta-hydroxysteroid dehydrogenase, respectively, showed significant increases in the former on both Days 2 and 7 and for the latter only on Day 7. This study supports the notion that sodium restriction decreases urinary cortisol excretion and provides evidence that increased activity of 5 beta-reductase and lowered metabolism by 11 beta-HSD are presumably the mechanisms of this decrease.
Steroids
PMID:Effect of sodium restriction on urinary excretion of cortisol and its metabolites in humans. 965 46

Apparent mineralocorticoid excess and licorice induced hypertension, both hypertensive disorders, have been attributed to a defect in the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which interconverts cortisol to cortisone. Therefore, we undertook this study to determine the role of human placental 11 beta-HSD activity in preeclampsia, which is a hypertensive disorder in pregnancy. 11 beta-HSD activities were determined in placentas of 17 normotensive and 11 preeclamptic patients matched for gestational age at 34-42 weeks. Cortisol levels in umbilical venous and arterial sera were also determined for both groups. Statistical analysis was performed using Student's t-test, significance at p < 0.05. 11 beta-dehydrogenase (oxidation activity of 11 beta-HSD) activity was significantly lower in placentas of preeclamptic compared to normotensive patients (0.19 +/- 0.09 vs. 0.26 +/- 0.08 mmoles/min/placenta, p = 0.02). Cortisol level in umbilical cord blood was significantly higher in the preeclamptic group (14.99 +/- 14.08 vs. 6.71 +/- 3.69 g/dL, p = 0.02). The decreased 11 beta-HSD activity is accompanied by an expected increase in umbilical cord blood cortisol level and decrease in fetal weight. This enzyme may play an important role in influencing fetal growth.
Steroids 1998 Oct
PMID:Placental 11 beta-hydroxysteroid dehydrogenase activity in normotensive and pre-eclamptic pregnancies. 980 Feb 81

In this study, we investigated whether progesterone exerts a local action regulating the function of the corpus luteum of pregnancy in rats. The luteal activities of the enzymes 3beta-hydroxysteroid dehydrogenase (3beta-HSD), involved in progesterone biosynthesis, and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), that catabolizes progesterone and reduces progesterone secretion by the corpus luteum, were evaluated after intrabursal ovarian administration of progesterone in pregnant rats that had received a luteolytic dose of prostaglandin F2alpha (PGF2alpha). Luteal 3beta-HSD activity decreased and 20alpha-HSD activity increased after PGF2alpha treatment (100 microg x 2 intraperitoneally on Day 19 of pregnancy at 12:00 p.m. and 4:00 p.m.) when compared with controls sacrificed at 8:00 p.m. on Day 20 of pregnancy. This effect of PGF2alpha on the luteal 3beta-HSD and 20alpha-HSD activities was abolished in animals that also received an intraovarian dose of progesterone (3 microg/ovary on Day 19 of pregnancy at 8:00-9:00 a.m.). In a second functional study, luteal cells obtained from 19-day pregnant rats responded to the synthetic progestin promegestone (R5020) in a dose-dependent manner, with an increase in the progesterone output. In addition, the glucocorticoid agent hydrocortisone did not affect progesterone accumulation in the same luteal cell culture. We also examined by immunocytochemistry the expression of progesterone receptors (PR) in the corpora lutea during pregnancy and demonstrated the absence of PR in this endocrine gland in all the days of pregnancy studied. In the same pregnant rats, positive staining for PR was observed in cells within the uteroplacental unit, such as cells of the decidua basalis and trophoblast giant cells of the junctional zone. In addition, positive PR staining was observed in the ovarian granulosa and theca cells of growing follicles, but not in corpora lutea of ovaries obtained from cycling rats at proestrus. In summary, this report provides further evidence of a local action of progesterone regulating luteal function in the rat despite the absence of a classic PR.
Steroids 1999 Nov
PMID:Progesterone receptor is not required for progesterone action in the rat corpus luteum of pregnancy. 1057 32

11Beta-hydroxysteroid dehydrogenase (11beta-HSD) Type I enzyme is found in testis and liver. In Leydig cell cultures, 11beta-HSD activity is reported to be primarily oxidative while another report concluded that is primarily reductive. Hepatic 11beta-HSD preferentially catalyzes reduction and the reaction direction is unaffected by the external factors. Recent analysis of testicular 11beta-HSD revealed two kinetically distinct components. In the present study, various steroid hormones or glycyrrhizic acid (GCA), given for 1 week, or thyroxine given for 5 weeks to normal intact rats had different effects on the 11beta-HSD oxidative activity in testis and liver. Deoxycorticosterone, dexamethasone, progesterone, thyroxine, and clomiphene citrate increased testicular 11beta-HSD oxidative activity, but decreased hepatic enzyme activity except for deoxycorticosterone (unchanged). Corticosterone and testosterone decreased 11beta-HSD oxidative activity in testis but not that of liver (which was unchanged). Estradiol, GCA and adrenalectomy lowered oxidative activity of 11beta-HSD in testis and liver, but the degrees of reduction were different. The in vivo effects of glucocorticoids too were different, even in the same organ. Dexamethasone, a pure glucocorticoid, has greater affinity for glucocorticoid receptors (GR) than corticosterone. The direct effects of dexamethasone via GR in increasing testicular 11beta-HSD oxidative activity may override its indirect effects. Possibly, the reverse occurs with corticosterone treatment, as it has both glucocorticoid and mineralocorticoid effects. Because both organs have Type I isoenzyme, the difference in 11beta-HSD oxidative activities of these two organs could be attributable to the presence of an additional isozyme in testis or differences in tissue-specific regulatory mechanisms.
Steroids 2000 Jan
PMID:Differential regulation of the oxidative 11beta-hydroxysteroid dehydrogenase activity in testis and liver. 1062 35

This study describes a new approach using stable isotope methodology in evaluating 11beta-HSD activities in vivo based on urinary excretion of cortisol, cortisone, and their A-ring reduced metabolites. The method involved the measurement of deuterium-labeled cortisol and its deuterium-labeled metabolites by GC/MS simultaneously with endogenous cortisol, cortisone, and their A-ring reduced metabolites after oral administration of deuterium-labeled cortisol to normal human subjects. This stable isotope approach offered unique advantages in assessing the appropriateness of measuring unconjugated and total (unconjugated + conjugated) cortisol, cortisone, and their A-ring reduced metabolites in urine as indices of renal 11beta-HSD2 activity in man. Our results strongly support that the measurement of urinary unconjugated cortisol and cortisone is a significant advance in assessing 11beta-HSD2 activity.
Steroids 2000 Feb
PMID:The use of deuterium-labeled cortisol for in vivo evaluation of renal 11beta-HSD activity in man: urinary excretion of cortisol, cortisone and their A-ring reduced metabolites. 1063 20

Steroids synthesized de novo from cholesterol in the brain are generally called neurosteroids. We have recently demonstrated, using biochemical and molecular biological methods, that certain structures in the quail brain possess cytochrome P450 side-chain cleavage enzyme (P450scc) and 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)-isomerase (3beta-HSD) and produce pregnenolone, pregnenolone sulfate and progesterone. To clarify the biosynthetic pathway of neurosteroids in the avian brain, therefore, we examined the expression of messenger RNA (mRNA) encoding for the enzyme cytochrome P450 17alpha-hydroxylase/c17,20-lyase (P450(17alpha,lyase)), which converts pregnenolone to dehydroepiandrosterone via 17alpha-hydroxypregnenolone or progesterone to androstenedione via 17alpha-hydroxyprogesterone. RT-PCR analysis followed by Southern hybridization indicated the expression of P450(17alpha,lyase) mRNA in the brain of sexually mature birds without a clear-cut sex difference. Employing biochemical techniques combined with HPLC analysis, the conversion of progesterone to 17alpha-hydroxyprogesterone was also found in brain slices of the mature male. P450(17alpha,lyase) mRNA was detected in various brain regions, but there was a clear regional difference in the expression. The expressions of P450(17alpha,lyase) mRNA in the diencephalon and mesencephalon were significantly higher than those in the cerebrum and cerebellum, unlike 3beta-HSD mRNA, which showed no regional difference in the expression. In situ hybridization revealed the cellular localization of P450(17alpha,lyase) mRNA. The cells expressing P450(17alpha,lyase) mRNA were detected several diencephalic and mesencephalic regions, such as the preoptic area, the anterior hypothalamus, the dorsolateral thalamus, the optic tectum and the ventral midbrain. The expression was also localized in the septum, the hyperstriatum accessorium, and the ventral portions of the archistriatum in the telencephalon. Cerebellar Purkinje cells also expressed P450(17alpha,lyase) mRNA. These results suggest that the avian brain possesses P450(17alpha,lyase) as well as P450scc and 3beta-HSD in both sexes. The expression of P450(17alpha,lyase) in the avian brain may be region-dependent.
 ...
PMID:Expression and localization of cytochrome P450 17 alpha-hydroxylase/c17,20-lyase in the avian brain. 1131 72

Organotin compounds are widely used as antifouling agents and bioaccumulate in the food chain. Tributyltin chloride (TBT) has been shown to induce imposex in female gastropods. On the basis of this observation it has been suggested that TBT acts as an endocrine disrupter inhibiting the conversion of androgens to estrogens mediated by the aromatase cytochrome P450 enzyme. However, to date, the molecular basis of TBT-induced imposex and in particular its putative inhibitory effects on human aromatase cytochrome P450 activity have not been investigated. Therefore, we examined the effects of the organotin compounds tetrabutyltin (TTBT), TBT, dibutyltin dichloride (DBT) and monobutyltin trichloride (MBT) on human placental aromatase activity. TBT was found to be a partial competitive inhibitor of aromatase activity with an IC(50) value of 6.2 microM with 0.1 microM androstenedione as substrate. TBT impaired the affinity of the aromatase to androstenedione but did not affect electron transfer from NADPH to aromatase via inhibiting the NADPH reductase. DBT acted as a partial but less potent inhibitor of human aromatase activity (65% residual activity), whereas TTBT and MBT had no effect. The residual activity of TBT-saturated aromatase was 37%. In contrast, human 3beta-HSD type I activity was only moderately inhibited by TBT (80% residual activity). Moreover, neither TTBT or DBT nor MBT inhibited the 3beta-HSD type I activity. Together, these results suggest that the environmental pollutants TBT and DBT, both present in marine organisms, textile and plastic products, may have specific impacts on the metabolism of sex hormones in humans.
Steroids 2001 Oct
PMID:Inhibition of human cytochrome P450 aromatase activity by butyltins. 1152 39


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